amylin and glucagon-like peptide-1 (glp-1): influence on gastric emptying, appetite and food intake in humans

Conditions: Diabetes

Summary: the aim of this proposal is to dissect the mechanisms controlling gastric emptying, appetite and food intake in humans, and to obtain new knowledge to fight obesity on a pharmacological basis.

the objective of the present study is to elucidate the mechanisms behind the effects of glucagon-like peptide-1 (glp-1) on gastric emptying, appetite and food intake. the first glp-1 based anti-diabetic therapy was approved by the fda in 2005 and is now on the market in the united states. the strong glucose-dependent insulinotropic property of glp-1 is a highly attractive feature in the pursue of optimal glycaemic control in type 2 diabetes. moreover, the potential of glp-1 to reduce gastric emptying, appetite and food intake makes it an attractive tool in the fight against obesity, a pandemic condition that often leads to type 2 diabetes, and several companies are developing weight lowering drugs based on glp-1. interestingly, another peptide, amylin, exerts very similar effects on gastric emptying, appetite and food intake in humans. amylin is found in insulin-rich granules in pancreatic beta-cells and is co-secreted with insulin upon insulinotropic stimuli. currently, it is not known whether the inhibiting effects of glp-1 on gastric emptying, appetite and food intake are directly mediated by glp-1, or if the effects are secondary to the robust insulin responses, and thereby amylin responses, elicited by glp-1. the objective of the present study is therefore to further elucidate the mechanisms of these effects in order to strengthen the development of anti-diabetic drugs with potential weight lowering capabilities.

Eligibility criteria:
inclusion criteria: * patients with type 1 diabetes * informed oral and written consent * caucasians over the age of 18 years with type 1 diabetes (diagnosed according to the criteria of who) receiving long acting insulin * c-peptide negative glucagon test * normal blood haemoglobin concentration * healthy control subjects * informed oral and written consent * caucasians over the age of 18 years * normal 75 g- oral glucose tolerance test (ogtt) according to the criteria of who * negative islet cell autoantibodies (ica) and gad-65 autoantibodies * no first-degree relatives with diabetes * normal blood haemoglobin concentration exclusion criteria: * patients with type 1 diabetes * residual beta-cell function (evaluated with glucagon test) * impaired hepatic function (aspartate aminotransferase (asat) and/or alanine aminotransferase (alat) \> 2 times upper normal limit) * diabetic nephropathy (serum-creatinine \> 130 µm and/or albuminuria) * diabetic neuropathy * proliferative diabetic retinopathy * pregnancy, breastfeeding or intention of becoming pregnant or judged to be using inadequate contraceptive measures * healthy control subjects * impaired hepatic function (asat or alat \> 2 times upper normal limit) * impaired renal function (serum-creatinine \> 130 μm and/or albuminuria) * first-degree relatives with diabetes * pregnancy, breastfeeding or intention of becoming pregnant or judged to be using inadequate contraceptive measures

Keywords: amylin glp-1 gastric emptying appetite and food intake